generic times: coagulation counseling

Author: Anna D. Garrett, PharmD, BCPS, CPP

Addition of leflunomide (Arava) to
warfarin therapy may result in a significant
increase in international normalized
ratio (INR). A recently published
case report involving a 61-year-old
patient with rheumatoid arthritis suggests
that inhibition of CYP2C9 by
leflunomide might be the mechanism
that causes this increase. The patient
had been stable on warfarin for the
4-month period prior to initiation of
leflunomide. She did not report any
changes in diet or medications that are
known to interact with warfarin. She
was being treated with prednisone and
sulindac, but no changes had been
made to her regimen during the time
period when the increase in INR to 7.3
was noted. Two doses of warfarin were
held, and her maintenance dose was
decreased over the
next 10 weeks from 36
to 28 mg/week.

Leflunomide is a prodrug
that is converted
to its active metabolite,
M1, in the liver and gut. M1 is a known
inhibitor of CYP2D9, the same isoenzyme
that metabolizes the S-isomer of
warfarin. M1 and warfarin are also highly
protein-bound, but no in vitro effects
on M1 by warfarin have been demonstrated.
Further study is needed regarding
this interaction, since there are no
human studies that have evaluated it.
Because the possibility of an interaction
exists, however, careful INR monitoring
should be performed when leflunomide
therapy is started in patients who are
on warfarin.

Dr. Garrett is a clinical pharmacistpractitioner at Cornerstone Health Carein High Point, NC.